The Influence of Genetic Background on the Expression of Mutations at the Diabetes Locus in the Mouse. V. Interaction between thedbGene and Hepatic Sex Steroid Sulfotransferases Correlates with Gender-Dependent Susceptibility to Hyperglycemia*

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Abstract
Steroid sulfurylation represents a potential mechanism for controlling the level of active steroids within a tissue. We have elucidated an inbred strain background-dependent interaction between the diabetes (db) mutation and steroid sulfotransferase (ST) enzymes, potentially modulating the level of active steroid hormones or their precursors in the liver. Gonadectomized mutants were analyzed to correlate how strain and gender-dependent variation in ST activities interacted with db to achieve diabetogenesis. Both sexes on the C57BL/KsChp(BKs) background developed severe early-onset hyperglycemia, and gonadectomy failed to prevent diabetes. In contrast, C3HeB/FeChp (C3HeB)-db/db males, but not females, were diabetes susceptible, and the male susceptibility was completely dependent upon endogenous testes-derived testosterone. The female resistance, in turn, was dependent upon ovarian sex steroids. The differential requirements of BKs- and C3HeB-db/db males and females for gonadal sex steroids could be explained on the basis of the differential strength of the interaction between the db mutation and hepatic ST activities. Hepatic ST from normal adult females sulfurylated dehydroepiandrosterone (DHEA), whereas this activity disappeared in cytosols of normal adult males by 8 weeks of age. This sexually dimorphic inability to sulfurylate (pre)androgens was controlled by testosterone. Diabetogenic susceptibility in BKs mutant mice of both sexes was associated with marked depression of preandrogen/androgen sulfurylation [female mutants exhibiting at least 5-fold reduced DHEA sulfuryation at a near-physiological concentration (0.2 .mu.M)]. This reduced preandrogen/androgen sulfurylation occurred concomitant with a 10-fold acceleration of estrone (E1) sulfurylation at a limiting (0.2 .mu.M) concentration, essentially producing a hyperandrogenized hepatic tissue state. These extreme shifts in ST substrate preferences were not observed in the diabetes-resistant C3HeB-db/db females. Kinetic analysis of semipurified hepatic ST from BKs-db/db females showed a 10-fold decrease in Km for E1 (apparent Km - 0.9 .mu.M in mutants vs. 9.0 .mu.M in normals). Whereas the Km for DHEA did not differ from the control value, hepatic ST from BKs-db/db females showed a 10-fold decreased maximal velocity for DHEA sulfurylation (1230 vs. 12750 pmol/mg.h in control preparations). The antihyperglycemic effects of dietary E1 therapy were associated with enhanced androgen sulfurylation in BKs-db/db females and restoration of androgen sulfurylation in BKs-db/db males. The finding that ST substrate preferences of 10-day-old m db/m db mice was unaffected clearly demonstrated that the db-mediated shifts in ST substrate preferences were not a direct consequence of the mutation, but were secondary to other metabolic changes occurring around puberty. In conclusion, we have correlated diabetogenic sensitivity to an interaction between the db mutation and sulfotransferases controlling the level of active steroid hormones or their precursors in the liver. Thus, structural or regulatory genes controlling ST qualify as major genomic modifiers of gender-dependent diabetes susceptibility in mice.